Hippocampal CysLT1R knockdown or blockade represses LPS-induced depressive behaviors and neuroinflammatory response in mice.

Evidence suggests that neuroinflammation is involved in depression and that the cysteinyl leukotriene receptor 1 (CysLT1R) plays a potential pathophysiological role in several types of CNS disorders. Our previous study has shown that knockdown of hippocampal CysLT1R in mice prevents the depressive-like phenotype and neuroinflammation induced by chronic mild stress (CMS). Here, we examined the effects of hippocampal CysLT1R knockdown and CysLT1R blockade on LPS-induced depressive-like behavior in mice. We found that injection of LPS (0.5 mg/kg, ip) caused marked increase in hippocampal CysLT1R expression, which was reversed by pretreatment with fluoxetine (20 mg·kg-1·d-1 for 7 d, ig). Knockdown of hippocampal CysLT1R or blockade of CysLT1R by pretreatment with pranlukast (0.5 mg/kg, ip) significantly suppressed LPS-induced depressive behaviors, as evidenced by decreases in mouse immobility time in the forced swimming test (FST) and tail suspension test (TST) and latency to feed in the novelty-suppressed feeding (NSF) test. Moreover, both CysLT1R knockdown and CysLT1R blockade markedly prevented LPS-induced neuroinflammation, as shown by the suppressed activation of microglia and NF-κB signaling as well as the hippocampal levels of TNF-α and IL-1ß in mice. Our results suggest that CysLT1R may be involved in LPS-induced depressive-like behaviors and neuroinflammation, and that downregulation of CysLT1R could be a novel and potential therapeutic strategy for the treatment of depression, at least partially due to its role in neuroinflammation.

Montelukast ameliorates streptozotocin-induced cognitive impairment and neurotoxicity in mice.

Extensive studies have demonstrated that neuroinflammation is associated with Alzheimer's disease (AD) and cysteinyl leukotriene receptor 1 (CysLT1R) was involved in neuroinflammation. Montelukast, a highly selective CysLT1R antagonist, has been reported to attenuate learning and memory impairments in the amyloid-ß-induced mouse model of AD. However, whether montelukast also exerts beneficial effects on streptozotocin (STZ)-induced memory deficits in mice is not well known. In the present study, we aimed to investigate the effects of montelukast on STZ-induced cognitive impairment, neuroinflammation and apoptosis in mice. Our data showed that intra-hippocampal microinfusion of STZ resulted in learning and memory impairments, including increased escape latency during acquisition trials and decreased exploratory activities in the probe trial in Morris watermaze (MWM) task, and decreased number of correct choices and increased latency to enter the shock-free compartment in Y-maze test, and caused neuroinflammatory and apoptotic responses, evidenced by increments of nuclear NF-κB p65, TNF-α, IL-1ß, cleaved caspase-3, Bax as well as decreased expression of Bcl-2 in hippocampus. Interestingly, STZ treatment led to up-regulation of protein and mRNA of CysLT1R in hippocampus. Of note, consecutive oral administration of montelukast (1 or 2mg/kg, 3 weeks) remarkably attenuated these effects induced by STZ. However, montelukast had no effect on normal mice. These results suggest that montelukast improves memory impairment and inhibits neuroinflammation and apoptosis in mice exposed to STZ. Montelukast may provide a novel strategy for treating or preventing AD.

Knockdown of hippocampal cysteinyl leukotriene receptor 1 prevents depressive behavior and neuroinflammation induced by chronic mild stress in mice.

RATIONALE: Numerous studies have demonstrated that neuroinflammation is associated with depression-like symptoms and neuropsychological disturbances, and cysteinyl leukotriene receptor 1 (CysLT1R) was reported to be involved in neuroinflammation. The pathophysiological role of CysLT1R has been reported in several types of brain damage. However, the role of CysLT1R in depression remains to be elucidated. OBJECTIVES: We aimed to investigate the effect of hippocampal CysLT1R downregulation on depressive behaviors and neuroinflammatory responses in mice exposed to chronic mild stress (CMS). RESULTS: We firstly found that expression of hippocampal CysLT1R was gradually increased over CMS exposure, while 3 weeks treatment with fluoxetine reversed the increment of hippocampal CysLT1R expression. Hippocampal CysLT1R knockdown suppressed CMS-induced depressive-like behaviors as evidenced by decreases in immobility time in tail suspension test (TST), decreased latency to feed in novelty-suppressed feeding (NSF) test, and by increase in the number of entries and decrease in time spent in the open arm in elevated plus maze (EPM) test. Increments of hippocampal NF-κB p65, IL-1ß, and TNF-α induced by CMS were also prevented by hippocampal CysLT1R knockdown beforehand. CONCLUSIONS: Hippocampal CysLT1R participates in depression, and knockdown of hippocampal CysLT1R prevents CMS-induced depressive-like behaviors and neuroinflammation, suggesting that suppression of CysLT1R could prevent the development of depression.

[Study on intestinal absorption features of oligosaccharides in Morinda officinalis How. with sigle-pass perfusion].

To study the in situ intestinal absorption of five oligosaccharides contained in Morinda officinalis How. (sucrose, kestose, nystose, 1F-Fructofuranosyinystose and Bajijiasu). The absorption of the five oligosaccharides in small intestine (duodenum, jejunum and ileum) and colon of rats and their contents were investigated by using in situ single-pass perfusion model and HPLC-ELSD. The effects of drug concentration, pH in perfusate and P-glycoprotein inhibitor on the intestinal absorption were investigated to define the intestinal absorption mechanism of the five oligosaccharides in rats. According to the results, all of the five oligosaccharides were absorbed in the whole intestine, and their absorption rates were affected by the pH of the perfusion solution, drug concentration and intestinal segments. Verapamil Hydrochloride could significantly increase the absorptive amount of sucrose and Bajijiasu, suggesting sucrose and Bajijiasu are P-gp's substrate. The five oligosaccharides are absorbed mainly through passive diffusion in the intestinal segments, without saturated absorption. They are absorbed well in all intestines and mainly in duodenum and jejunum.

In vivo reflectance confocal microscopy of Basal cell carcinoma: feasibility of preoperative mapping of cancer margins.

BACKGROUND: Reflectance confocal microscopy (RCM) images skin at cellular resolution and has shown utility for the diagnosis of nonmelanoma skin cancer in vivo. It has the potential to define lesion margins before surgical therapy. OBJECTIVES: To investigate the feasibility of RCM in defining the margins of basal cell carcinoma before surgery. METHODS: The margins of 10 lesions were evaluated using RCM. Biopsies of the margins were used to confirm the results. A protocol was constructed to define margins. RCM was used to delineate preoperative surgical margins in 13 patients. Intraoperative frozen biopsy was used to confirm the margins. RESULTS: In seven of 10 (70.0%) cases, the margins of the cancer were identified suing RCM. The tumor island was the critical feature in identifying the margins. In 12 of 13 (92.3%) cases, frozen biopsy corroborated that the surgical margins delineated by RCM were clear. CONCLUSION: RCM imaging of the margins is feasible and demonstrates the possibility of preoperative mapping of cancer margins.

In vivo reflectance confocal microscopy of extramammary Paget disease: diagnostic evaluation and surgical management.

BACKGROUND: Extramammary Paget disease (EMPD) is a diagnostic challenge. In vivo reflectance confocal microscopy (RCM) has been reported to be useful for in vivo skin tumor evaluation. It may also assist in the surgical management of EMPD lesions. OBJECTIVE: We sought to describe confocal features of EMPD and correlate them with histopathologic findings. The potential of RCM to map the lesions for subsequent surgical management was also investigated. METHODS: A total of 23 lesions from 14 recruited patients were evaluated by RCM and histopathologic examination. RCM was used to delineate preoperative surgical margins in two patients. RESULTS: Erythematous, hyperpigmented, and hypopigmented lesions were evaluated by RCM and results were confirmed by histopathologic examination. Paget cells were observed throughout the epidermis. Typical Paget cells on RCM were characterized by a mild bright nucleus and dark cytoplasm, frequently twice the size of keratinocytes or larger. At the dermoepidermal junction, tumor nests were seen as dark glandular structures. A high density of dendritic cells was observed in pigmented lesions and a low density in erythematous lesions. Dilated vessels and inflammatory cells were seen in pigmented and erythematous lesions. Paget cells within the epidermis and nest structures at the dermoepidermal junction were seen in most lesions. These two features were useful for delineating the margins. Histologic examination corroborated the surgical margins found by RCM. LIMITATIONS: The sensitivity and specificity of these diagnostic features have not been fully studied, and differential diagnostic features require exploration. CONCLUSION: Features correlating well to histopathology are observed on the RCM of EMPD lesions. RCM may be used as an auxiliary diagnostic tool for the diagnosis and management of EMPD.

[HILIC-eLSD determination of five oligosaccharides contained in Morinda officinalis].

OBJECTIVE: To determine determinate five oligosaccharides, namely sucrose, 1-kestose, nystose, 1F-fructofurano-syinystose, bajijiasu contained in Morinda officinalis with an HILIC-ELSDI) method. METHOD: Waters XBridge Amide (4.6 mm x 150 mm, 3.5 microm) hilic column was adopted for gradient elution, with acetonitrile (A) and 0.2% triethylamine (B) as the mobile phase. The column temperature was set at 40 degrees C, with the flow rate of 0.8 mL x min. Waters 2424 evaporative light scattering detector (ESLD) was used as detector, with the gas flow of 275.79 kPa and drift tube temperature of 90 degrees C. RESULT: The detection range for the five oligosaccharides were 2.128-21.28 microg for sucrose (r = 0.999 3), 1.864-18.64 microg for 1-kestose (r = 0.999 6), 1.92-19.2 microg for nystose (r = 0.999 8), 1.912-19. 12 microg for 1F-fructofuranosyinystose (r = 0.999 5), 2.368-23.68 microg for bajijiasu (r = 0.999 4), respectively. The recovery of the five oligosaccharides ranged between 92.81%-102.8% (n = 6). CONCLUSION: The method is so simple, accurate and highly reproducible that it can be used as an analytical method for effective evaluation of the quality of M. officinalis herbs.